PROJECT SUMMARY Critical illness, a hypercoagulable state, and the presence of a central venous catheter are the 2 most important risk factors for deep venous thrombosis in children. Catheter-associated deep venous thrombosis (CADVT) is associated with increased length of stay in the intensive care unit, increased cost of care, and increased risks of pulmonary embolism and death. Yet, given the lack of evidence to demonstrate benefit, prophylaxis against CADVT is not recommended in children. The recommendation to provide prophylaxis against thrombosis in critically ill adults should not be routinely applied to children without pediatric evidence because the hemostatic system and co-morbidities vastly differ between adults and children. Randomized controlled trials are urgently needed to determine whether prophylactic anticoagulation can safely prevent CADVT in critically ill children. However, the timing and level of anticoagulation needed to achieve this are unclear. The goal of this R21 application is to assess the efficacy of early prophylaxis, at standard dose, against CADVT in critically ill children to determine if it should be further tested in a phase 3 trial. We will use enoxaparin, the standard prophylaxis in children, adjusted by anti-Xa level to achieve this goal. Aim 1 is to obtain preliminary evidence on the effect of early prophylaxis on the incidence of CADVT in critically ill children. We hypothesize that among critically ill children, prophylaxis administered <24 hours after insertion of the catheter decreases the incidence of ultrasound-diagnosed CADVT compared with no prophylaxis. The natural history of CADVT and prior trials suggest that prophylaxis needs to be administered <24 hours after the insertion of the catheter to prevent CADVT. We propose a phase 2b trial in which children admitted to the intensive care unit with a newly inserted central venous catheter will be randomized to standard prophylactic dose of enoxaparin vs. no prophylaxis. We will use Bayesian decision-theoretic paradigm to decide whether to proceed with a phase 3 trial of early prophylaxis with enoxaparin at standard dosing. Aim 2 is to evaluate the effect of an anti-Xa level-directed prophylactic strategy on thrombin generation in critically ill children. We hypothesize that among critically ill children, standard prophylactic dose of enoxaparin adjusted by anti-Xa level reduces thrombin generation to <700 nM.min, as measured by endogenous thrombin potential. Thrombin generation, which assesses the level of anticoagulation, is best measured by endogenous thrombin potential. In non-critically ill adults, prophylactic dose of enoxaparin proven to prevent thrombosis reduces endogenous thrombin potential to <700 nM.min. We propose a longitudinal study measuring endogenous thrombin potential at multiple time points in all children in the phase 2b trial. Bayesian inference will be used to inform of modifications in dosing that may be needed for a phase 3 trial. The proposed research challenges the current paradigm on prophylaxis against CADVT in children. Our findings will inform the success and design of a pediatric phase 3 trial of early prophylaxis against CADVT.